Full Text HL-97-003 PEDIATRIC CARDIOVASCULAR DISEASE NIH GUIDE, Volume 26, Number 3, January 31, 1997 RFA: HL-97-003 P.T. 34 Keywords: Cardiovascular Diseases Children (Patients) Adolescents National Heart, Lung, and Blood Institute Letter of Intent Receipt Date: June 30, 1997 Application Receipt Date: December 11, 1997 PURPOSE This solicitation invites grant applications to enter a single open competition for Specialized Centers of Research (SCOR) in pediatric cardiovascular disease. This program is open to all investigators, including those who are participating in the current program and those who are not. The objective of this initiative is to foster interdisciplinary studies of the etiology, pathophysiology and diagnosis of congenital and acquired cardiovascular disease in children in a context that will lead to more effective methods of treatment and prevention. To this end, investigators must present applications that encompass both basic and clinical science, and include studies of patients. Those studies must be designed to comply with NIH policies regarding gender and ethnicity unless exceptions can be scientifically justified. HEALTHY PEOPLE 2000 The Public Health Service (PHS) is committed to achieving the health promotion and disease prevention objectives of "Healthy People 2000", a PHS-led national activity for setting priority areas. This RFA, Pediatric Cardiovascular Disease, is related to the priority areas of maternal and infant health, heart disease and stroke, diabetes and chronic disabling diseases, and immunization and infectious diseases. Potential applicants may obtain a copy of "Healthy People 2000" (Full Report: Stock No. 017-001-00474-0 or Summary Report: Stock No. 017-001-00473-1) through the Superintendent of Documents, Government Printing Office, Washington, DC 20402-9325 (telephone 202-512-1800). ELIGIBILITY REQUIREMENTS Applications may be submitted by domestic for-profit and non-profit institutions, public and private, such as universities, colleges, hospitals, and laboratories. The principal investigator should be an established research scientist with the ability to ensure quality control and the experience to administer effectively and integrate all components of the program. A minimum time commitment of 25 percent is expected for this individual. The principal investigator must also be the project leader of one of the component research projects. If, through peer review, this project is not recommended for further consideration, the overall SCOR application will not be considered further. If this project is judged by peer review to be of low scientific merit, it will markedly reduce the overall scientific merit ranking assigned to the entire application by the review committee. Project leaders must agree to commit at least 20 percent effort to each project for which they are responsible. MECHANISM OF SUPPORT This RFA will use the National Institutes of Health (NIH) specialized center of research grant mechanism (P50). Responsibility for planning the proposed project will be solely that of the applicant. The total project period for an application submitted in response to this RFA may not exceed five years. The anticipated date of award is January 1, 1999. Upon initiation of the program, there will be required communications between SCORs, usually in the setting of a meeting of SCOR participants. Therefore, in the preparation of the budget, applicants should request travel funds for this purpose in fiscal years 1999, 2000, 2001, and 2002 of the budget. Applicants should include a statement in their applications indicating their willingness to participate in these meetings. FUNDS AVAILABLE New applications may request up to $1,140,000 direct costs, not including indirect costs for collaborating institutions, in the first year, with a maximum increase of no more than three percent in each future year requested in the application. Competing renewal applications may request no more than 10 percent above the direct costs awarded in the final budget period or $1,140,000, whichever is greater. It is anticipated to support three SCOR grants for a five year project period at an estimated first year total cost of $3.22 million. Award of grants pursuant to this RFA is contingent upon receipt of funds for this purpose. Designated funding levels are subject to change at any time prior to final award, due to unforeseen budgetary, administrative, and/or scientific developments. Equipment is included in the budget limitation. However, requests for expensive special equipment that cause an application to exceed this limit may be permitted on a case-by-case basis following staff consultation. Such equipment requires justification. Final decisions will depend on the nature of the justification and the availability of funds. RESEARCH OBJECTIVES Background According to the recent report of the American Heart Association Task Force on Children and Youth, cardiovascular disease affects more than 600,000 infants, children and youths in the United States. This number includes patients with congenital cardiovascular malformations (CCVM), inherited progressive disorders such as Marfan's syndrome and hypertrophic cardiomyopathy, cardiac dysrhythmias and conduction disorders, and acquired diseases such as Kawasaki disease and rheumatic heart disease. Recent studies in flies, fish, frogs and mice have identified a large number of genes that are involved in cardiac and vascular morphogenesis, although for the most part the gene products and their functions have yet to be identified. In parallel with these discoveries, progress has been made in understanding the etiology of congenital heart disease with the important discovery that, contrary to earlier hypotheses, there is a relatively high incidence of inherited heart defects and many of these are single gene defects. However, as with animal studies, the gene products and their functions have yet to be elucidated. Thus, the field is now poised for fruitful collaborations between basic and clinical investigators who seek knowledge of how mutated or deleted genes perturb normal development. A goal of the SCOR program is to forge between experimental embryologists and clinical scientists a link that will rapidly increase knowledge of possible causes of CCVM and lead to new treatment and prevention strategies. For a number of different cell types, significant progress has been made in understanding the molecular control of the life and death of a cell. However, the genes involved in proliferation of cardiac myocytes, their differentiation, withdrawal from the cell cycle, and programmed cell death remain to be elucidated. Furthermore, it is not known whether manipulation of gene expression could cause cardiac myocytes to re-enter the cell cycle or avoid apoptosis. Such research could provide an important foundation toward repair and regeneration of cardiac muscle in patients with myocardial cell deficiency as in hypoplastic left heart syndrome or cell loss resulting from disease. The potential for gene therapy for cardiac muscle defects and disease would be increased by such studies. The clinical health of the myocardium is determined by genetic and environmental factors. Adverse effects of these factors could result in dysfunction of myocytes, fibroblasts and endocardial endothelium. Injury may result from toxic agents, infections, inflammatory cells and neurohormonal influences. Little is understood of the effects of such factors and the possibilities of etiology-specific prevention strategies and therapeutics have yet to be explored. Immunologic rejection is a major cause of death and morbidity in pediatric cardiac transplantation. Immunologic factors may also be crucial in the pathogenesis of coronary vascular disease following transplantation. Studies to define mechanisms of these events in pediatric patients and to alter their occurrence by therapeutic interventions will be crucial in improving outcome. Arrhythmias are a substantial cause of mortality and morbidity in pediatric patients. Recently, molecular genetic studies of familial arrhythmias have been fruitful. Several genetic loci causing the long QT syndrome have been mapped and mutations in cardiac sodium and potassium channels defined. The mechanisms by which these mutations are arrhythmogenic need to be elucidated. Other familial rhythm disorders (WPW syndrome and RV dysplasia) are being studied by similar techniques. The etiologies and treatments of sporadic and post-operative arrhythmias remain as inviting challenges for investigation. Furthermore, little is known about the genes that control the initiation of the heart beat and development of conduction system or how the products of those genes control function of the heart. Recent success in the in utero repair of lung defects, congenital diaphragmatic hernia and resection of congenital cystic adenomatoid malformations gives good reason to expect that similar results could be obtained for serious congenital cardiovascular malformations. Moreover, second trimester clinical fetal surgery has shown that tissue hypoplasia can be reversed if correction is made early. If the goal of early intervention is to be achieved, considerable effort must be placed on the detection of malformations earlier in fetal development than the current limit of 18 to 22 weeks of gestation for diagnosis of congenital heart defects by echocardiography . Early and accurate visualization of cardiac defects, for instance by ultrasound or MRI, would allow the option of in utero intervention, either by surgery or percutaneously delivered catheters, or perhaps ultimately by local delivery of constructs or genetically altered cells. Fetal somatic gene therapy with local delivery of vectors expressing essential genes or genetically altered cells may eventually prove to be the least traumatic way to alter aberrant cardiovascular development. In the meantime, refinement of current imaging techniques and miniaturization of interventional catheters for use in fetal therapy is essential. There is increasing evidence that a spectrum of congenital cardiovascular malformations and alterations in myocardial growth and function may be the result of maternal-fetal interactions. Important environmental influences include maternal diabetes, maternal systemic lupus erythematosus, maternal toxemia/placental insufficiency, cocaine addiction, HIV, alcoholism, and poor nutrition. Very little is known about the physiological effects of altered hemodynamics and changes in the hormonal, immune, and growth factor environment on the developing embryo and fetus. These topics are for illustrative purposes only. Applicants are expected to develop programs based on their knowledge of the field, their expertise and availability of patients. Basic and Clinical Research The overall concept of a SCOR program focuses on scientific issues related to diseases relevant to the mission of the NHLBI. It is essential, therefore, that all applications include both basic and clinical research projects. In the ideal SCOR, the basic research derives from, or is otherwise intimately linked to, the clinical research proposed by the investigators. Interactions between basic and clinical scientists are expected to strengthen the research, enhance transfer of fundamental research findings to the clinical setting, and identify new research directions. Plans for transfer of findings from basic to clinical studies should be described. Each SCOR grant application and award must include research involving human/patient subjects. Support may be provided for human biomedical studies of etiology, pathogenesis, prevention and prevention strategies, diagnostic approaches, and treatment of diseases, disorders or conditions. Small population-based studies, where the research can be completed within five years, may also be proposed. In addition, basic research projects must be included that relate to the clinical focus. A SCOR may also contain one or more core units that support the research projects. SPECIAL REQUIREMENTS Exclusions This RFA is intended to support Specialized Centers of Research grants. A SCOR provides the opportunity for investigators to engage in interdisciplinary and collaborative research which is focused on a specific disease or an area within a disease category. It is required that SCOR applications include studies of human subjects and/or human materials as well as basic studies clearly related to a disease area. The foundation of the clinical component should be strongly linked to the basic science projects; the basic science studies should be driven by the needs of the clinical projects. Thus, a SCOR has a central theme to which all research projects pertain. In addition, a SCOR may include CORE units to provide services to the various research projects and to support the organizational and administrative aspects of the program. Applications that include only basic or only clinical research will not be responsive to this RFA. In addition, clinical research projects focused on large epidemiological studies or large clinical trials will be considered unresponsive to this RFA. Awards will not be made to foreign institutions. However, under exceptional circumstances, a foreign component critical to a project may be included as a part of that project. In addition, to encourage women and underrepresented minority investigators to work within a SCOR project, to facilitate recruitment of new scientists to this area of research, and to foster cutting edge and innovative research directions, each SCOR program may support up to two investigators by utilizing up to $50,000 direct costs per year per investigator to fund pilot and feasibility projects. This will allow underrepresented minority investigators to acquire skills and data to make them more competitive in seeking independent research support (e.g. R01, R29). These funds will not be supplements, but rather specific dollars identified in the SCOR budget and restricted to be used for this purpose. The recipients would be chosen based on a proposal written by a SCOR investigator and reviewed by an internal review committee at the parent institution. Applicants should be aware that applications for supplemental funds will be accepted only under unusual and well defined circumstances. For example, the NHLBI may provide supplements to Centers to continue a project not funded for the entire project period. NHLBI staff must be consulted prior to submission of an application for supplemental funds. Supplemental grants for these purposes will not be awarded for the first 18 months or the last 12 months of a total project period. Length of SCOR Programs The National Heart, Lung, and Blood Advisory Council, at its meeting in September 1992, recommended that each NHLBI SCOR program be limited to ten years of support. Exceptions to this policy will be made only if a thorough evaluation of needs and opportunities, conducted by a committee composed of non-federal experts, determines that there are extraordinarily important reasons to continue a specific SCOR program. Thus, under this policy, a given SCOR grant is awarded for a five-year project period following an open competition. Only one five-year competing renewal is permitted, for a total of ten years of support, unless the SCOR program is recommended for extension. The NHLBI comprehensive evaluation of the SCOR program in Pediatric Cardiovascular Disease will be conducted during the second project period according to the following schedule: Project Period (Second Competition) FY 1999 to FY 2003 Letters to SCOR Directors regarding FY 2001 (mid-way through year 02 SCOR evaluation Plans of 2nd project period) SCOR Evaluation Meeting FY 2001 (Late in year Notification of SCOR Directors FY 2002 (mid-way through year 03 of NHLBI decision period 2nd project period) Number of Applications The NHLBI does not limit the number of SCOR applications in a given SCOR program from one institution provided there is a different SCOR principal investigator for each application and each application is self-contained and independent of the other(s). This does not preclude cooperation among participants of SCORs after awards are made. Scientific overlap among applications will not be accepted. If more than one application is envisioned from an institution, the institution is encouraged to discuss its plans with the NHLBI SCOR program administrator. Consortium Arrangements If a grant application includes research activities that involve institutions other than the grantee institution, the program is considered a consortium effort. Such activities may be included in a SCOR grant application, but it is imperative that a consortium application be prepared so that the programmatic, fiscal, and administrative considerations are explained fully. The published policy governing consortia is available in the business offices of institutions that are eligible to receive Federal grants-in-aid. Consult the latest published policy governing consortia before developing the application. If clarification of the policy is needed, contact Mr. William Darby, Section Chief, Grants Operation Branch, NHLBI, (301) 435-0177. Applicants should exercise great diligence in preserving the interactions of the participants and the integration of the consortium project(s) with those of the parent institution, because synergism and cohesiveness can be diminished when projects are located outside the group at the parent institution. Indirect costs paid as part of a consortium agreement are excluded from the limit on the amount of direct costs that can be requested. At least 50 percent of the projects and cores and their associated costs must be at the parent institution. INCLUSION OF WOMEN AND MINORITIES IN RESEARCH INVOLVING HUMAN SUBJECTS It is the policy of the NIH that women and members of minority groups and their subpopulations must be included in all NIH supported biomedical and behavioral research projects involving human subjects, unless a clear and compelling rationale and justification is provided that inclusion is inappropriate with respect to the health of the subjects or the purpose of the research. This policy results from the NIH Revitalization Act of 1993 (Section 492B of Public Law 103-43). All investigators proposing research involving human subjects should read the "NIH Guidelines for Inclusion of Women and Minorities as Subjects in Clinical Research," which have been published in the Federal Register of March 28,1994 (FR 59 14508-14513), and reprinted in the NIH Guide for Grants and Contract, Volume 23, Number 11, March 18, 1994. LETTER OF INTENT Prospective applicants are asked to submit, by June 30, 1997 a letter of intent that includes a descriptive title of the proposed research, the name, address, and telephone number of the principal investigator, the identities of other key personnel and participating institutions, and the number and title of the RFA in response to which the application may be submitted. Although a letter of intent is not required, is not binding, and does not enter into the review of subsequent applications, the information that it contains is helpful in planning for the review of applications. The letter of intent is to be sent to: Dr. James Scheirer Division of Extramural Affairs National Heart, Lung, and Blood Institute 6701 Rockledge Drive, Room 7220, MSC 7924 Bethesda, MD 20892-7924 Telephone: (301) 435-0266 FAX: (301) 480-3541 Email: James_scheirer@NIH.gov Upon receipt of the letter of intent, applicants will be contacted by program staff to discuss their proposed applications and to provide guidance to applicants not familiar with the SCOR concept. APPLICATIONS PROCEDURES The research grant application form PHS 398 (rev. 5/95) is to be used in applying for these grants. Applications kits are available at most institutional offices of sponsored research and may be obtained from the Division of Extramural Outreach and Information Resources, National Institutes of Health, 6701 Rockledge Drive, MSC 7910, Bethesda, MD 20892-7910, telephone 301/710-0267, email: ASKNIH@odrockm1.od.nih.gov. In addition potential applicants should contact Dr. Constance Weinstein, at the address listed under INQUIRIES, to obtain supplemental instructions for modifying the forms to accommodate a SCOR application. Applicants must follow these instructions for their application to be considered responsive. Applicants from institutions that have a General Clinical Research Center (GCRC) funded by the NIH National Center for Research Resources may wish to identify the GCRC as a resource for conducting the proposed research. If so, a letter of agreement from either the GCRC program director or principal investigator should be included with the application. The RFA label available in the PHS 398 application form must be affixed to the bottom of the face page of the application. Failure to use this label could result in delayed processing of the application such that it may not reach the review committee in time for review. In addition, to identify the application as a response to this RFA, check "YES", enter the title, "Specialized Center of Research: Pediatric Cardiovascular Disease," and the RFA number HL-97-003 on Line 2 of the face page of the application. Send or deliver a signed, typewritten original of the application, including the checklist, and three signed photocopies, in one package to: DIVISION OF RESEARCH GRANTS NATIONAL INSTITUTES OF HEALTH 6701 ROCKLEDGE DRIVE, SUITE 1040 - MSC 7710 BETHESDA, MD 20892-7710 BETHESDA, MD 20817 (for courier/express service) Send two additional copies of the application to Dr. James Scheirer, Review Branch, at the address listed under LETTER OF INTENT. It is important to send these two copies at the same time as the original and three copies are sent to the Division of Research Grants, otherwise the NHLBI cannot guarantee that the application will be reviewed in competition for this RFA. Applications must be received by December 11, 1997. If an application is received after that date, it will be returned to the applicant. The Division of Research Grants (DRG) will not accept any application in response to this RFA that is essentially the same as one currently pending initial review, or is essentially the same as one already reviewed. This does not preclude the submission of substantial revisions of applications already reviewed, but such applications must include an introduction addressing the previous critique. REVIEW CONSIDERATIONS Upon receipt, applications will be reviewed for completeness by DRG and for responsiveness by the NHLBI. Incomplete and/or non- responsive applications will be returned to the applicant without further consideration. Applications that are complete and responsive to the RFA will be evaluated for scientific and technical merit by a peer group convened by the NHLBI in accordance with the review criteria stated below. As part of the initial merit review, a process may be used by the initial review group in which applications will be determined to be competitive or non-competitive based on their scientific merit relative to other applications received in response to the RFA. Applications judged to be competitive will be discussed and be assigned a priority score. Applications determined to be non-competitive will be withdrawn from further consideration and the principal investigator/program director and the official signing for the applicant organization will be notified. Neither site visits nor reverse site visits are planned as a part of the review process, therefore each application must be complete on submission. Rosters of NHLBI reviewers are listed on the NHLBI Homepage at http://www.nhlbi.nih.gov/meet/sep/devlop.asc. The review criteria for this RFA are: o the scientific merit of each proposed project in the application, including originality, feasibility of the approach, and adequacy of the experimental design; o the integration of the clinical and fundamental research into a coherent enterprise with adequate plans for interaction and communication of information and concepts among the collaborating investigators; o the technical merit and justification of each core unit; o the qualifications, experience, and commitment of the SCOR Director and his/her ability to devote adequate time and effort to provide effective leadership; o the competence of the investigators to accomplish the proposed research goals, their commitment, and the time they will devote to the program; o the adequacy of facilities to perform the proposed research including the laboratory and clinical facilities, access to subjects, instrumentation, and data management systems when needed; o the scientific and administrative structure of the program, including adequate internal and external arrangements and procedures for monitoring and evaluating the proposed research and for providing ongoing quality control and scientific review; o the institutional commitment to the program and the appropriateness of the institutional resources and policies for the administration of a research program of the type proposed; and o the appropriateness of the budget for the proposed program. AWARD CRITERIA Applications must fulfill all the eligibility criteria in order to be considered for funding. Since a variety of approaches would represent valid responses to this RFA, it is anticipated that there will be a range of costs among individual grants awarded. The most important criterion in selecting awardees will be the scientific merit as reflected in the priority score. However, factors such as program balance and available funds may enter into selection from among meritorious applications. Schedule Letter of Intent Receipt Date: June 30, 1997 Application Receipt Date: December 11, 1997 Review by NHLBAC: September 3-4, 1998 Anticipated Award Date: January 1, 1999 INQUIRIES Inquiries concerning this RFA are encouraged. The opportunity to clarify any issues or questions from potential applicants is welcome. Direct inquiries regarding programmatic issues to: Dr. Constance Weinstein Division of Heart and Vascular Diseases National Heart, Lung, and Blood Institute 6701 Rockledge Drive, Room 9144 - MSC 7940 Bethesda, MD 20892-7940 Telephone: (301) 435-0510 FAX: (301) 480-1335 Email: weinstec@gwgate.nhlbi.nih.gov Inquiries regarding fiscal and administrative matters may be directed to: Mr. William Darby Division of Extramural Affairs National Heart, Lung, and Blood Institute 6701 Rockledge Drive, Room 7128 - MSC 7926 Bethesda, MD 20892-7926 Telephone: (301) 435-0177 FAX: (301) 435-3310 Email: William_darby@nih.gov AUTHORITY AND REGULATIONS This program is described in the Catalog of Federal Domestic Assistance No. 93.837, Heart and Vascular Diseases. Awards will be made under the authorization of the Public Health Service Act, Title IV, Part A (Public Law 78-410, as amended by Public Law 99-158, 42 USC 241 and 285) and administered under PHS grants policies and Federal Regulations 42 CFR 52 and 45 CFR Part 74. This program is not subject to the intergovernmental review requirement of Executive Order 12372 or Health Systems Agency review. The PHS strongly encourages all grant and contract recipients to provide a smoke-free workplace and promote the non-use of all tobacco products. In addition, Public Law 103-227, the Pro-Children Act of 1994, prohibits smoking in certain facilities (or in some cases, any portion of a facility) in which regular or routine education, library, day care, health care or early childhood development services are provided to children. This is consistent with the PHS mission to protect and advance the physical and mental health of the American people. .
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